Control of acetylcholine receptors in skeletal muscle

Abstract

An ACh receptor is the molecular entity that, in its native habitat, possesses the binding sites for ACh and all the other components required to generate the ion channels mediating the ACh response. Narrower definitions of an ACh receptor (as the binding site for ACh or the polypeptide chain that is folded to form the binding site) could lead to semantic arguments about receptor structure. Experimentally, ACh receptors are defined by their total function (when electrophysiological tests are used) or by ligand binding. There is no evidence that the ligand-binding portions of ACh receptors ever exist in vivo without the associated channel-forming mechanism and vice versa. Most data are consistent with the idea that detergent-solubilized glycoproteins retaining the ACh binding sites of the receptor also include the channel-forming components, although it appears that the mechanism is prone to denaturation or proteolytic damage. Studies of receptor-rich membranes and of solubilized receptor glycoprotein have not yet yielded a totally satisfactory image of receptor structure. Most evidence favors an ACh receptor composed of three or four different types of glycosylated polypeptide chains organized into a unit of aggregate molecular weight about 300,000--400,000 daltons. Plasma membranes are dynamic structures in two different ways. First, their constituent molecules are in rapid thermal motion and, when these molecules are not tethered to extramembranous structures or mired in large aggregates, they fairly rapidly change their position in the plane of the lipid bilayer. Second, all membrane components are continually being synthesized and degraded. Acetylcholine receptors participate in both aspects of this dynamism. In this review it is proposed that the number and the distribution of ACh receptors in skeletal muscle are controlled by modulation of receptor metabolism and modulation of associations between receptor molecules or between receptors and other, as yet unidentified, elements in neuromuscular junctions and at extrajunctional sites where receptors are clustered. The arrangements of receptors in skeletal muscle and the total number of receptors in skeletal muscle may be regulated by separate mechanisms. Clusters of ACh receptors apparently can form spontaneously in extrajunctional areas of denervated muscles and in tissue-cultured embryonic muscle. Such clusters may be positionally stable and the receptor molecules in them may be highly restricted in mobility. Nevertheless, these receptors have average lifetimes on the order of 20 h, just like the nonclustered, mobile extrajunctional receptors. Receptor clusters also form at sites of innervation. In the chick embryo the junctional receptor molecules remain short-lived. The metabolism of ACh receptors is highly regulated. The biosynthesis of receptors commences during myogenesis at about the time myogenic cells become competent to fuse. Later, biosynthesis is dramatically repressed by muscle activity and possibly by other factors...